A growing line of evidence suggests the importance of the intrauterine environment for mammary carcinogenesis. Maternal overweight and obesity are likely among the most important perinatal predictors of breast cancer risk. Numerous studies have associated high birthweight, which is linked to high maternal body mass index (BMI), with an increased risk of breast cancer among premenopausal women. Insulin-like growth factor (IGF)-II plays a major role in embryonic and fetal development and growth. IGF2 is an imprinted gene expressed only by the paternal allele. Loss of imprinting (LOI) of IGF2 during reprogramming due to DNA hypomethylation leads to biallelic expression, resulting in increased IGF-II production and extreme fetal growth through increased cell proliferation and reduced apoptosis.The LOI of IGF2 has been associated with the development and growth of breast cancer. Biallelic IGF2 expression has been found in breast tissue and in normal tissue and lymphocytes from breast cancer patients. The obese and diabetic intrauterine environment fosters a high birthweight and high cord blood levels of insulin and leptin. Leptin metabolism may be programmed in utero and determine circulating leptin levels throughout the life course. High leptin levels have been associated with an increased risk of breast cancer.Using cord blood samples from the labor floor in our department we will examine the role of maternal overweight and obesity in LOI of IGF2. Using data from the Nurses' Health Study II on birthweight, blood samples obtained prior to diagnosis of cancer, and confirmed cases of premenopausal breast cancer among the nurses, we will explore the mediating role of leptin. We propose to test the following hypotheses: 1) a high maternal BMI is associated with a significantly increased LOI of IGF-2 in the daughter, and 2) The association between a high birthweight and an increased incidence of premenopausal breast cancer is partially mediated through leptin plasma levels. [unreadable] [unreadable] [unreadable]